In Kraepelin's pioneering diagnostic system, dementia praecox was divided from manic depressive psychosis. Although modern psychiatry has continued to effectively use this dichotomous classification, there is increasing evidence of connections between the 2 disorders. Some symptoms of the disorders are similar, there appears to be some genetic overlap, and many of the psychopharmacologic interventions are effective in both disorders. The evolving understanding of this interface and the implications for psychopharmacologic interventions will be discussed.

Historical Background

In Kraepelin's groundbreaking conceptual schema of 1919, dementia praecox was differentiated from manic-depressive psychosis.[1] He based his observations on the clinical course over decades in more than 1000 patients, and he included both symptomatic as well as longitudinal elements. The process of dementia referred to Kraepelin's observation of extensive difficulties in perceptual as well as cognitive areas of function, and praecox to the early onset of the disorder.[2] The progressive downhill course was one of the characteristics that Kraepelin thought distinguished the disorder from the periods of normal function he noted in manic-depressive psychoses. Despite his pessimistic prognostic view, he recognized that a small percentage did not deteriorate or showed improvement.[3]

In 1911, Bleuler coined the term "schizophrenia," derived from the Greek, indicating a "splitting of the mind."[4] The process of splitting referred to the separation of normally integrated psychic functions that coordinated thought, affect, and behavior. This splitting was viewed as occurring as the personality lost its logical unity and sense of connectedness. Pathognomonic symptoms were seen as primary to the diagnosis. In contrast to Kraepelin, Bleuler stressed the variability in course and referred to "the schizophrenias" to emphasize these differences between individuals. Blunted affect, loosening of associations, ambivalence, and autism were seen as core features of the disorder. Bleuler considered symptoms such as delusions and hallucinations secondary symptoms since they occurred in disorders other than schizophrenia and were viewed as reactions to internal or environmental states.

Kurt Schneider also advocated core pathognomonic features of schizophrenia that he termed "first-rank" symptoms.[5] These symptoms included hearing one's thoughts spoken aloud; auditory hallucinations commenting on one's own behavior; thought withdrawal, insertion, and broadcasting; and somatic hallucinations, or the experience of one's thoughts as being controlled or influenced from the outside.

Prior to the DSM-III, the diagnostic symptoms in the United States suffered from vague descriptions and ill-defined criteria, resulting in unreliable diagnostic categories. In an attempt to introduce rigor into the classification system, the DSM-III system was based on narrowly defined, standardized diagnostic categories that could be easily and reliable communicated to researchers and clinicians. The validity of the diagnostic divisions could then be scientifically tested. The Kraepelinian distinction between schizophrenia and bipolar disorder was maintained in the DSM. However, pathognomonic signs were also considered central. Only 1 symptom needed to be present for 6 months if the individual experienced "bizarre" delusions or hallucinations, 2 or more voices conversing, or the Schneiderian first-rank symptom of a voice keeping a running commentary on a person's behavior or thoughts.

The introduction of the modern DSM system advanced our research initiatives and clinical understanding of the disorders. However, the insistence on discretely defined, observable criteria has also limited our vision in appreciating the interfaces between disorders. The DSM system also neglects information about the etiology and pathophysiology that could serve to further refine our diagnostic categories.[2] The science of psychiatry has advanced rapidly in the last several decades, and we must now incorporate new data from brain imaging techniques, molecular biology, psychopharmacologic insights, genetics, and other disciplines. Armed with this new information, we may now re-evaluate our conceptual distinctions in a more rigorous and scientifically based way.

Genetic Evidence

There is clear genetic evidence of the heritability of both bipolar disorder and schizophrenia. Family studies have repeatedly demonstrated that probands of individuals with bipolar disorder have a higher lifetime risk of affective disorders. In a family study, 60 offspring were assessed from families with at least 1 bipolar parent.[6] The rate of psychiatric disorders in the children was 51% and included ADHD, major depression or dysthymia, and bipolar disorder. In families with a bipolar child, the parents tended to have earlier symptom onset. In families where 2 parents had bipolar disorder, the offspring had increased severity of depressed as well as irritable mood, a lack of mood reactivity, and rejection sensitivity. The offspring in these cases, however, did not have an increase in grandiosity, euphoria, or diminished need for sleep. Bipolar parents who had a history of attention-deficit/hyperactivity disorder (ADHD) during childhood tended to have children with bipolar disorder rather than ADHD. There are clear symptoms overlapping between ADHD and bipolar disorder, including impulsive behavior, problems with attention, and hyperactivity. Many patients are either misdiagnosed with ADHD or are comorbid for the disorder.[7] ADHD may therefore be a marker for early-onset mania in some children.[8] In a meta-analysis of 17 studies, the offspring of parents with bipolar disorder were 4 times more likely to develop an affective disorder.[9] The risk of developing any psychiatric disorder was increased 2.7 times.

Schizophrenia has also been shown to have strong genetic components. In a study comparing monozygotic vs dizygotic twins in Finland, an estimated 83% of the variance in liability to schizophrenia was due to genetic factors and 17% to environmental factors.[10] In another study, 723 first-degree relatives of individuals with schizophrenia were compared with 1056 matched surgical controls. There was more than an 18-fold risk increase in the relatives of schizophrenics compared with controls. There was also an increased risk of schizoaffective disorder, paranoid disorder, and atypical psychosis, but not unipolar depression, anxiety disorders, or alcoholism.[11]

Despite the evidence of differential inheritance patterns of schizophrenia and bipolar disorder, there also appear to be some areas of genetic overlap. Both disorders are inherited in a polygenetic fashion, with multiple genes determining the risk of developing the disorder.[12] Both disorders have been noted in some families, and schizoaffective disorder is present at a higher rate in families with either disorder.[13,14] There appear to be some shared genetic elements that may result in similar psychopathologic presentations (eg, psychosis), although the overall genetic patterns may differ between patients afflicted with either disorder.[15] Several regions of the human genome have been implicated in both disorders, such as loci 18p11.2 and 22q11-13.[14,16]

Psychopathologic Connections

There is also psychopathologic evidence of overlap in the 2 disorders. Psychosis is common in bipolar disorder, and approximately half of manic episodes are accompanied by psychotic features. In a survey of pediatric-onset bipolar disorder, the rate of psychotic symptoms varied from 16% to 87.5%, depending on the age of the subjects and nature of the population.[17] Psychotic symptoms may be mood-congruent or mood-incongruent, and congruity had no prognostic value in one study.[18] Other research, however, compared patients with mood-incongruent psychosis during a manic episode vs individuals with either mood-congruent delusions or those with no psychotic symptoms for a period of 8 months. Mood-incongruent psychotic features were associated with more persistent psychosis and poorer functioning during the 8-month follow-up period.[19] The percent of weeks with affective symptoms did not differ, however. Schneiderian first-rank symptoms have been noted in bipolar disorder and therefore are not pathognomonic of schizophrenia as had originally been posited. In hospitalized patients with bipolar disorder, 31% of males and 14% of females showed first-rank symptoms.[20]

Psychopharmacologic Evidence

Neuroleptics have been the mainstay of treatment for schizophrenia since the introduction of chlorpromazine in the 1950s. The atypical agents are now the treatment of choice due to their generally more benign side-effect profile and lower incidence of tardive dyskinesia.[21] There is an evolving role for the use of atypical neuroleptics in the bipolar spectrum disorders as well, even in the absence of psychosis.[22,23] Several trials have indicated that the addition of atypical neuroleptics to mood stabilizing medications, such as lithium or valproate, may result in a more robust response.[24,25] The atypical agents are also useful as stand-alone agents and may be equivalent in effectiveness to classical mood stabilizers in some cases. All of the atypical agents have been approved in both disorders, except for aripiprazole in bipolar disorder. Thus, the similarity of treatment options provides further evidence of a clinical continuity in some areas. The exact mechanisms that underlie this broad therapeutic response to the atypical agents require further elucidation.

Clinical Differences in Atypical Agents

The atypical agents all share greater 5-HT(2A) receptor affinity than D(2) receptor affinity, and this is thought to differentiate them from the typical agents.[26] However, each of the atypical agents possesses a unique pharmacologic profile that results in differing therapeutic effects and side effect profiles. With the broad array of agents now available, the clinician must weigh both the therapeutic benefits and negative effects of interventions.[27]

Improvements in anxiety as well as depression have been noted with several of these agents.[28,29] Ziprasidone may have particular effectiveness in ameliorating anxiety and mood since it possesses affinity for serotonin and norepinephrine reuptake sites.[30,31] Improvement in cognition has been noted with the atypical agents,[32] but there may be some differential effects in this regard. For example, in one study, patients treated with conventional antipsychotics, olanzapine, or risperidone were switched due to suboptimal efficacy or poor tolerability. Significant improvement on ziprasidone was noted on measures of secondary verbal memory compared with the baseline measures in all 3 groups. Patients switched from either conventional agents or risperidone experienced improvement in vigilance as well as executive function. Verbal fluency also improved in some patients.[33] In another study, however, a difference was not noted in cognitive function in inpatients with schizophrenia or schizoaffective disorders treated with either ziprasidone or olanzapine.[34] Further controlled head-to-head studies are required to more rigorously evaluate this area.

Side Effect Profile

It has become increasingly evident that there is a wide variability in the tendency of the atypical agents to induce metabolic abnormalities, including weight gain, hyperlipidemia, and diabetes.[35] Since patients with schizophrenia and bipolar disorder are at higher baseline risk for these health problems prior to initiation of treatment, particular care should be exercised with these populations. Olanzapine and clozapine have repeatedly induced the most weight gain compared with other atypical agents.[36] On the other hand, neither ziprasidone nor aripiprazole have been noted to induce weight gain.[37] In a comparison of the atypical agents drawn from 81 studies after 10 weeks of treatment at standard doses, weight gain with clozapine was 4.45 kg; olanzapine, 4.15 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg.[38] Olanzapine and clozapine are also the most likely to induce hyperlipidemia, while ziprasidone does not increase levels.[31,39]

Increases in glucose levels and type 2 diabetes have been reported with the atypical agents, and, as with weight gain, the risk appears to be greatest with olanzapine and clozapine.[40-42] In a summary of 45 new-onset cases of diabetes, approximately 44% were secondary to clozapine and 42% secondary to olanzapine. The rates on risperidone and quetiapine were each approximately 7%,[43] 84% presented within 6 months of starting treatment, and 42% of the total sample presented with diabetic ketoacidosis (DKA). Those presenting with DKA were significantly younger and less overweight at the start of therapy. There was a higher proportion of women in the DKA cohort compared with those presenting with new-onset diabetes alone. DKA resulting in death in individuals has been reported with olanzapine as well as clozapine.[44-46]

Summary and Conclusions

Despite the clear symptomatic and course differences in patients with schizophrenia and bipolar disorder, it is also becoming increasingly evident that there are many similarities. This evidence may be noted in family studies, genetic analysis, common symptom complexes, psychopharmacologic responses, as well as other areas. Further elucidation of these overlapping features is important to more exactly differentiate syndromes and more closely tailor therapeutic options to specific symptom complexes in both disorders. The variety of the currently available atypical neuroleptics allows for a more exacting administration to achieve the broadest clinical effectiveness while minimizing side effects in both disorders.

__________________Be nice to me, I have powers and Andrew no longer compensates me with shoes!! Do what you feel in your heart to be right - for you'll be criticized anyway. You'll be damned if you do, and damned if you don't.--Eleanor RooseveltI'm all in favor of keeping dangerous weapons out of the hands of fools. Let's start with typewriters. --Frank Lloyd Wright Everything I write is fully substantiated by my personal opinion.